FIELD OF THE INVENTION
[0001] The present invention is directed to the use of bubbles and, more particularly, to
imaging through the use of bubbles.
BACKGROUND OF THE INVENTION
[0002] Photoacoustics is an emerging field within medical imaging. As photoacoustics relies
on detection of the acoustic waves generated via optical absorption and the consequent
heating/expansion process, the technology is closely tied to ultrasound. Typically,
an intensity modulated light source, or short pulse source (i.e., laser), is used
as the excitation source. The light is typically shined at the tissue surface, but
can also be delivered from inside by means of minimally invasive delivery systems
(e.g., endoscope, catheter, light-delivery needle). It penetrates the tissue predominantly
via light scattering, thus illuminating a large volume. The light gets absorbed by
blood/tissue chromophores, or non-targeted and targeted exogenous contrast agents
such as optical dyes or nanoparticles configured for this purpose. The absorption,
and consequent expansion, produces the acoustic wave, i.e., ultrasound or acoustic
signal. The blood vessels (with different sizes and densities within a tumor, as well
as different blood oxygenation level) and the surrounding tissue differ as to their
light absorption. The resulting difference in the optically generated ultrasound produced
provides contrast used in imaging. The technique's popularity is seen to be growing
rapidly within the research community, focusing around some preclinical work such
as whole body small animal imaging and monitoring pharmacokinetics, and clinical applications
in oncology such as for breast or prostate cancer.
[0003] However, commonly-assigned International Publication Number
WO 2009/057021 to Wang et al., (hereinafter "Wang"), entitled "Photoacoustic Imaging Contrast Agent and System
for Converting Optical Energy to In-Band Acoustic Emission", which is incorporated
herein by reference in its entirety, notes, and illustrates therein by Figs. 1(a),
1(b), 2(a), 2(b), that photoacoustic (PA) signals generated by irradiating, with short
laser pulses, a point absorber such as a PA contrast agent particle, are broadband,
and only a fraction of the PA signal energy falls within the receive frequency range
of a regular medical ultrasound transducer. A largely predominant portion of the energy
falls outside the range, i.e., into a higher frequency range.
[0004] To address this, Wang places microbubbles and/or nanobubbles in close proximity of
the PA contrast agent.
[0005] In particular, each nanoparticle in Wang incorporates evaporating material and light-absorbing
material. When the light-absorbing material is excited or "activated" by irradiation,
it evaporates its evaporating material to thereby create an attached bubble.
[0006] Advantageously, the system can be tuned so that the bubbles re-radiate the energy
principally within the receive frequency range of a regular medical ultrasound transducer.
The energy re-radiated has been amplified, and has spread out in all directions, including
in the direction of an ultrasound transducer.
[0007] The nanoparticles, before activation, are small enough to cross the boundary between
the vasculature and lymphatic system. Accordingly, permeability can be measured. Also
as a consequence, more anatomy can be imaged.
[0008] Material from which a bubble is formed, and the light-absorbing material that causes
formation of the bubble, are combined in a particle, or droplet, in ways that differ
according to the embodiment, thereby collectively offering a range of bubble size,
and of bubble longevity over repeated expansions.
[0009] US 6,662,040 B1 discloses a method of generating an image of an animate human or non-human animal
body or part thereof. The method comprises administering to said body a physiologically
tolerable contrast agent comprising a radiation absorbing component and/or a pressure
inducing component, exposing said body to radiation, detecting pressure waves generated
in said body by said radiation and generating an optoacoustic image therefrom of at
least a part of said body containing the administered contrast agent.
[0010] US 5,977,538 A discloses further optoacoustic systems and methods for performing diagnostic and
therapeutic imaging.
[0011] WO 2010/020939 A2 discloses a monitoring system which includes a transducer and a wireless interface.
The transducer receives ultrasonic imaging signals reflected from a target and provides
imaging data based on the received imaging signals. The wireless interface communicates
the imaging data over a wireless communications network to a host device.
[0013] Post-published document
WO 2011/045734 A1 discloses a photoacoustic contrast agent based active ultrasound imaging method and
device.
SUMMARY OF THE INVENTION
[0015] The present inventors have observed that, in addition to the above -discussed bandwidth
mismatch problem, conventional PA imaging of an object, such as a cyst, a heart or
a lymph node, primarily identifies merely the tissue boundaries, as the technique
relies on differential optical absorption. The differential absorption creates respectively
differential expansion in the tissue. The ultrasound generated at the boundary, by
the expansion, will tend to be less visible to the extent the boundary faces away
from the ultrasound transducer. Accordingly, only the insonification-direction boundaries
are clearly visible.
[0016] What is proposed herein is an extension of Wang and is directed to addressing one
or more of the concerns described above.
[0017] As proposed herein, a bubble, as in Wang, is positioned in close proximity of a PA
contrast agent such as a dye-based or nanostructured PA contrast agent, and likewise
re-radiates acoustic energy omni-directionally. Accordingly, the above-noted angle
dependence in imaging is analogously overcome, with the bubbles filling tissue structures
so as to aid in their visualization, so that an ultrasound transducer can be utilized
to more fully detect the structure based on the ultrasound received from the bubbles.
[0018] In addition, in the current proposal, the bubble is free floating and can be pre-made,
affording more flexibility as to size and longevity. Yet, the bubble can still function
to relay acoustic energy provided by nano-sized particles that have permeated to areas
microbubbles are too big to reach. With regard to size, the scattering cross-section
of a bubble is a few orders (up to 10
6) greater than its geometrical cross-section, allowing contrast microbubbles closely
surrounding a point PA source to effectively intercept the acoustic energy to be relayed.
[0019] According to claim 1, the present invention relates to a use of a photoacoustic system
together with an imaging contrast agent which has been pre-administered to a body
tissue,
the photoacoustic system comprising a laser, an ultrasound transducer array, and a
control unit,
the imaging contrast agent comprising microbubbles and a first photoacoustic contrast
agent which is comprised in nanoparticles, wherein said nanoparticles are separately
free-floating from said microbubbles,
wherein the laser is used to repeatedly emit laser pulses to the body tissue to cause
pulses of acoustic energy from the nanoparticles,
wherein the ultrasound transducer array is used to receive ultrasound transmitted
from oscillations of the microbubbles in the body tissue, which oscillations are caused
by the pulses of acoustic energy from the nanoparticles,
wherein the ultrasound transducer array is further used to transmit ultrasound pulses
to the body tissue and to receive relayed ultrasound pulses which are relayed by the
microbubbles in response to said transmitted ultrasound pulses,
wherein the control unit is used to localize the microbubbles in the body tissue based
on said received ultrasound and said received relayed ultrasound pulses.
BRIEF DESCRIPTION OF THE DRAWINGS
[0020]
Fig. 1 is a schematic and conceptual diagram of an exemplary photoacoustic system;
and
Fig. 2 is a flow chart which illustrates operation of the system in Fig. 1.
DETAILED DESCRIPTION OF EMBODIMENTS
[0021] A photoacoustic (PA) system 100, as shown in Fig. 1 by way of illustrative and non-limitative
example, includes, as an imaging array, an ultrasound transducer array 102 connected
by a cable to a control unit 104. The transducer array 102 comprises a spatial distribution
of transducer elements (not shown). The control unit 104 can include, as control electronics,
one or more integrated circuits (ICs) as a controller 106, and optionally, for receiving
control information, an antenna 108 and/or a wire input 110. The controller 106 is
connectable communicatively with the transducer array 102, as by the cable or a wireless
connection. The antenna 108 receives control information transmitted by a source antenna
112. The control information is formed by varying 1 14 an electrical current of an
electrical circuit 116. The control information, if fed to the control unit 104, may
also be conveyed by a wired connection to the wire input 110.
[0022] Microbubbles 118, 120, 122, which can serve as an ultrasound (US) contrast agent
123, are shown in Fig. 1 free floating in body tissue 124. The body tissue 124 can
free-floating from said microbubbles, wherein the nanoparticles cause pulses of acoustic
energy in response to being irradiated by the laser pulses,
wherein the microbubbles transmit ultrasound pulses in response to being oscillated
by the pulses of acoustic energy generated by the nanoparticles, and wherein the microbubbles
relay ultrasound pulses transmitted from the ultrasound transducer array,
wherein the ultrasound transducer array is further configured to receive the ultrasound
pulses transmitted and relayed by the microbubbles, and
wherein the photoacoustic system further comprises a control unit for reconstructing
a photoacoustic ultrasound image based on the received ultrasound pulses transmitted
and relayed by the microbubbles.
[0023] What is proposed herein is realizable as methods, compositions of matter for carrying
out the methods, devices for performing the methods, computer programs for carrying
out the functionality of the devices, signals for conveying the functionality, and/or
methods for generating the signals. A method for generating a signal comprises varying
an electrical current applied to at least one of: a) a wire input to said device;
and b) an antenna for transmitting, so as to, by the varying, generate the signal.
[0024] Details of the novel, photoacoustic contrast agent technology are set forth further
below, with the aid of the following drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
[0025]
Fig. 1 is a schematic and conceptual diagram of an exemplary photoacoustic system;
and
Fig. 2 is a flow chart which illustrates operation of the system in Fig. 1.
DETAILED DESCRIPTION OF EMBODIMENTS
[0026] A photoacoustic (PA) system 100, as shown in Fig. 1 by way of illustrative and non-limitative
example, includes, as an imaging array, an ultrasound transducer array 102 connected
by a cable to a control unit 104. The transducer array 102 comprises a spatial distribution
of transducer elements (not shown). The control unit 104 can include, as control electronics,
one or more integrated circuits (ICs) as a controller 106, and optionally, for receiving
control information, an antenna 108 and/or a wire input 110. The controller 106 is
connectable communicatively with the transducer array 102, as by the cable or a wireless
connection. The antenna 108 receives control information transmitted by a source antenna
[0027] 112. The control information is formed by varying 1 14 an electrical current of an
electrical circuit 116. The control information, if fed to the control unit 104, may
also be conveyed by a wired connection to the wire input 1 10.
[0028] Microbubbles 118, 120, 122, which can serve as an ultrasound (US) contrast agent
123, are shown in Fig. 1 free floating in body tissue 124. The body tissue 124 can
be that of a medical patient or, more generally, that of a human or animal subject
or of a specimen.
[0029] Microbubbles, having diameters of from 1 to 5 microns on average, are often confined
to the vasculature, although some are small enough to pass into the lymphatic system.
Nanoparticles 126, 128, 130, 132, 134, 136, 138, which comprise a PA contrast agent
or "acoustic energy source"140, are small enough to make the passage. The nanoparticles
126-138 may be of any known and suitable type serving as a PA contrast agent, e.g.,
gold or carbon nano-rods or nano-spheres.
[0030] The nanoparticle 126 is shown within a tissue structure 142 that the microbubbles
118 may be too big to reach.
[0031] The microbubble 118 is positioned at a physical separation from, but is close enough
to, the nanoparticle 128 that the short PA pulse travels merely a short distance before
energizing the microbubble. Thus, attenuation loss at this proximity is small. Also,
the PA pulse is broadband, and relatively little acoustic attenuation loss occurs
in biological tissue with respect to comparatively lower acoustic frequencies to be
relayed. Accordingly, the microbubble 118 intercepts and re-radiates the acoustic
energy, acting as a nonlinear acoustic energy converter and as an acoustic signal
amplifier.
[0032] The same can be said for the other microbubbles 120, 122 shown in Fig. 1, and for
their nearby nanoparticles 130, 136, respectively, which are other portions of the
source 140 of acoustic energy, that energy arising due to the application of the current
laser pulse. At least a portion of the source 140 is to be imaged.
[0033] Pulse-echo imaging of the microbubble 118-122 need not rely on a pulse from the ultrasound
transducer array 102. Instead, in the case of photoacoustics, the original pulse is
from the laser (not shown) which may be repeatedly emitting laser pulses.
[0034] The pulse-echo imaging used here, unlike that already used in photoacoustics, is
based on ultrasound relayed (scattered or reflected) from bubbles, and proceeds as
follows. The laser pulse causes a pulse of acoustic energy from the nearby nanoparticle
128, 130, 136 which, in turn, causes oscillation of the nearby bubble 118-122. The
oscillation transmits ultrasound that is received by the transducer array 102. The
original laser pulse travels with the speed of light which is much faster than acoustic
wave propagation speed. It is also assumed that the nanoparticle 128, 130, 136 is
negligibly close to its respective microbubble 118-122. Thus, time delay or "time-of-flight"
(TOF) between the laser pulse and a particular element of the transducer array 102
can be visualized as the magnitude of a radius to a partial spherical surface concentric
with the element, with the microbubble 118-122 located somewhere on the spherical
surface. Multiple ones, or all, of the elements can have their own spherical surfaces
for that particular microbubble 118-122. Conversely, each of the microbubbles 118-122
has its own respective set of spherical surfaces, each surface corresponding to its
own element. TOF from microbubbles at different distances from a given element can
be distinguished by an increase, during the reception time window, in received acoustic
pressure magnitude. Two spherical surfaces of respective transducer elements intersect
to form a curved line, and a third one may intersect with the line to form a point.
For each point formed from the above-noted spherical surfaces, an increment of "light"
is assigned. Some points in the body tissue, or "volume of interest" (VOI) 124, therefore
have light, and, incrementally, some more than others. The points with the most light
are geometrically localized in the VOI as the positions of the microbubbles 118-122.
In summary, the microbubble 118, 120 or 122 relays (scatters/reflects) ultrasound
pulses from a nearby PA source (as in PA imaging) at the location of the nanoparticle
128, 130 or 136, respectively, the locations of the microbubbles 118-122 becoming
known according to nearby nanoparticles 128, 130 and 136 that are very close to the
respective microbubbles.
[0035] Later-arriving radiofrequency data from the each of the microbubbles 118-122 may
be distinguished based again on an increase of the observed acoustic pressure magnitude
during the receive time window. The arriving data can be indicative of the nanoparticle
138, for those situations in which the microbubbles are not located immediately near
the nanoparticle, i.e., the relatively larger microbubbles are unable to reach certain
tissue structures. From the already-localized microbubbles 118-122 partial spherical
surfaces whose radius respectively reflects the additional TOF can be used to likewise
triangulate and thereby localize the "remote" nanoparticle 138. Accordingly, angles
144, 146, 148 and respective physical separations, or equivalently, TOFs 150, 152,
154 are utilized to localize the remote nanoparticle 138. The angles 144-148 represent
the directions in which acoustic energy emitted by the PA contrast agent, or "source",
140 is relayed by the microbubbles 118-122 to the respective elements of the transducer
array 102. Indirectly, the previously-determined TOFs 156, 158, 160 to the microbubbles
118-122 are also used in the localization. The TOFs 156-160 are shown as corresponding
to respective elements of the transducer array 102, but the same analysis can be performed
over multiple elements.
[0036] It should be pointed out that, because the distance between the microbubble 118 (or
120 or 122) and the nanoparticle 138 is much less than the distance between the microbubble
118 (or 120 or 122) and the array 102, the microbubbles 118-122 still act as acoustic
signal enhancers for the nanoparticle 138 of the source 140.
[0037] Note that the microbubbles 118-122 can also relay (scatter/reflect) ultrasound pulses
transmitted from the array 102 (as in ultrasound imaging). Thus, the locations of
the microbubbles 118-122 can be determined with, e.g., microbubble-specific ultrasound
contrast imaging. The localization of microbubbles as in ultrasound contrast imaging,
in turn, makes it much more convenient and accurate to determine the locations of
nanoparticles (such as the nanoparticle 138) as in the PA imaging. In addition, a
higher frame rate for ultrasound imaging, if required, can be achieved using fewer
broad beams (one very broad beam in the limiting case) for transmitted ultrasound
pulse sequences.
[0038] Also, although three microbubbles 118-122 are used in the example, more may be used
in the calculation if more have data to contribute. Additionally, other nanoparticles
126 are disposed at locations of the PA contrast agent 140 for being imaged. Thus,
these other nanoparticles 126 can likewise be localized to fill out the imaging of
the microbubble-inaccessible region.
[0039] Thus, the first PA contrast agent 140, even when in a non-activated state, constitutes,
when combined with the microbubbles 118-122, a second PA contrast agent 162. Here,
the first PA contrast agent 140 is separately free-floating from the microbubbles
118-122, even when the two are joined by mixing them together.
[0040] Contrast coverage 164 at the site 166 to be imaged extends beyond the tissue structure
142 to include the microbubbles 118-122 in the example shown in Fig. 1.
[0041] Multiple scattering 168 of acoustic energy between microbubbles 118, 120 as shown
in Fig. 1, will distort the imaging. The multiple scattering 168 is to be minimized
by decreasing bubble concentration while maximizing the contrast coverage 164 by increasing
the concentration.
[0042] Operationally, and with reference to Fig. 2, a receive bandwidth for the medical
ultrasound application is determined (step S204). Imaging deeper lesions, for example,
will require a band of lower ultrasound frequencies at the expense of resolution.
Conversely, interrogating shallower objects can be done with a bandwidth that includes
higher frequencies. Since the resonance frequency of a bubble varies inversely with
its size, a range of bubble sizes is then selected to come within the receive frequency
range of the ultrasound transducer array 102 (step S208).
[0043] Mixing/administration of the US contrast agent 123 with the selected bubble sizes
is performed (step S212).
[0044] There are a number of different possible ways this can be done.
[0045] The PA contrast agent or "first group" 140 can, e.g., in a non-activated state, be
mixed with the US contrast agent or "second group" 123 to form the second PA contrast
agent 162.
[0046] The mixing may be performed during, and/or just before, the clinical examination,
although at this stage of the current example the mixing occurs just before the examination,
and it can be performed internally, i.e., within the patient or subject, or externally.
For example, the first group 140 and the second group 123, after being diluted, may
fill two separate syringe pumps. The timing and rate of injection of each group, as
by infusion by means of an intravenous catheter (IV), can be controlled by each pump
independently. The output of the two pumps is mixed to form the PA contrast agent
162 and then infused either directly, or indirectly by means of a saline infusion
line, into the patient. The infusion can occur before and/or during the imaging examination.
Timing and dosage for each group 140, 123 can be independently controlled. The mixing
has the effect of positioning the US contrast agent 123, by virtue of the consequent
proximity of the microbubbles 118-122 to respective nanoparticles 126-138, for relaying
acoustic energy received that was emitted by the source 140. The US contrast agent
123 remains so positioned after infusion.
[0047] Alternatively, the patient can be infused or injected with a combination of the two
groups 140, 123 that was pre-mixed substantially prior to the imaging examination.
Here, too, the mixing positions the ultrasound contrast agent 123, by virtue of the
consequent proximity of the microbubbles 118-122 to respective nanoparticles 126-138,
for relaying acoustic energy received that was emitted by the source 140. Likewise,
the US contrast agent remains so positioned after infusion.
[0048] It is also possible for one group 140, 123 to be infused systematically into the
bloodstream while another group is directly injected into the object, e.g., lesion,
so that the onset of mixing occurs internally.
[0049] As a further example, both groups 140, 123 are injected or infused directly into
the object at the same time or at different times.
[0050] A patient, alternatively, could ingest both groups 140, 123 concurrently or separately
in, for example, the case of intestinal imaging. Or, perhaps, the groups 140, 123
could be, as another example, injected, through the urethra, into the kidneys, of
PA examination of the kidneys.
[0051] In any event, the mixing and/or the administration timing or rate may be performed
so as to, with respect to the imaging site 166, maximize contrast coverage 164 while
minimizing multiple scattering 168 between microbubbles 118-122.
[0052] The site 166 can be monitored by ultrasound contrast agent pulse-echo imaging to
detect when the microbubbles 118-122 have filled the site sufficiently for the examination
(step S216), at which point in time a laser pulse can be fired at the site (step S220).
The acoustic energy thereby produced is relayed for reception by the ultrasound transducer
array 102 (step S224).
[0053] The laser pulsing and reception steps S220, S224 can be done repeatedly to accumulate
more data for analysis (step S228). Optionally, the laser pulsing step S220 may, at
times, include the above-described microbubble-specific ultrasound contrast imaging
as a technique alternative to PA imaging for localizing the microbubbles 118-122,
the technique being performed to update the localization.
[0054] When the pulsing and reception steps S220, S224 are not to be repeated, such as at
a pause to check results (step S228), or, alternatively, while they continue to be
repeated, the user can make, in real time under imaging guidance, an adjustment to
the mixing and/or administration timing or rate to more fully realize the concurrent
goals of contrast coverage maximizing and multiple scattering minimizing (step S232).
The imaging guidance can involve monitoring microbubble concentration that exists
at the imaging site 166, by microbubble-specific ultrasound contrast imaging for example.
[0055] Then, if examination is to continue (step S236), processing returns to step S220;
otherwise, if examination is not to continue, the procedure terminates.
[0056] Bubbles are utilized in some embodiments as part of a photoacoustic contrast agent
and, in some embodiments, to localize one or more locations of a source of acoustic
energy. The bubbles, such as microbubbles, can be used in proximity of nanoparticles
of a first photoacoustic contrast agent, thereby affording a second photoacoustic
contrast agent. The bubbles can intercept and re-radiate acoustic energy emitted by
light-based activation of the first photoacoustic contrast agent in the immediate
vicinity of the bubbles. As a further option, if the nanoparticles permeate further
to tissue structures but remain in close enough proximity, their positions can be
triangulated by the nearby bubbles, based on direction and time delays of ultrasound
received by a transducer array.
[0057] Although methodology according to what is proposed herein can advantageously be applied
in providing medical diagnosis for a human or animal subject, the intended scope of
claim coverage is not so limited. More broadly, enhanced photoacoustic imaging, in
vivo, in vitro or ex vivo is envisioned.
[0058] The proposed technology is directly applicable to cardiovascular imaging and oncology,
which are the usual target application areas for PA imaging.
[0059] While the invention has been illustrated and described in detail in the drawings
and foregoing description, such illustration and description are to be considered
illustrative or exemplary and not restrictive; the invention is not limited to the
disclosed embodiments.
[0060] For example, nano-bubbles may be used in place of microbubbles in any or all of what
is proposed above.
[0061] Other variations to the disclosed embodiments can be understood and effected by those
skilled in the art in practicing the claimed invention, from a study of the drawings,
the disclosure, and the appended claims. In the claims, the word "comprising" does
not exclude other elements or steps, and the indefinite article "a" or "an" does not
exclude a plurality. Any reference signs in the claims should not be construed as
limiting the scope.
[0062] A computer program can be stored momentarily, temporarily or for a longer period
of time on a suitable computer-readable medium, such as an optical storage medium
or a solid-state medium. Such a medium is non-transitory only in the sense of not
being a transitory, propagating signal, but includes other forms of computer-readable
media such as register memory, processor cache and RAM.
[0063] A signal embodying the above-described inventive functionality of the device 100,
and for conveying it to the device, is formable by appropriately varying an electrical
current. The signal can arrive by a device input wire, or be transmitted wirelessly
by an antenna.
[0064] A single processor or other unit may fulfill the functions of several items recited
in the claims.